Numerous family and epidemiological studies support the role of genetic factors in schizophrenia. With the development of powerful molecular biological techniques, increasing effort has been placed upon the identification of the molecular basis of a putative genetic abnormality. Genetic association studies examine the relationships between allelic variants in "candidate" genes and particular illnesses or clinical manifestations of illness that are not necessarily an etiologic factor. The association approach is therefore particularly well-suited for the identification of genes involved in a clinically heterogeneous illness such as schizophrenia. Statistical comparison between allelic frequencies in affected patients and controls is fundamental to the association approach. The use of control subjects recruited from the general population results in ethnic differences between patient and control groups that can confound interpretation of results. The best strategy to ensure the validity of significant associations is utilization of the "haplotype relative risk" (HRR) design. With HRR, DNA is collected from an affected individual and the parents of the affected subject. The four chromosomes of the parents containing a specific locus provide the relevant information for the study. The two chromosomes that are transmitted to me affected child are defined as "disease chromosomes" with the remaining two chromosomes comprising the control group. Our work is focusing on two areas of investigation: 1) Allelic variation in schizophrenia -- We have examined polymorphisms in the dopamine and serotonin receptor genes for association with schizophrenia using the HRR strategy. This work involves DNA collection from over one hundred and fifty schizophrenic patients and their parents. We have completed studies of the role of 5HT2A receptor, serotonin transporter, D3 receptor, and Apolipoprotein E polymorphisms in schizophrenia. Moreover, we are continuing a study of the glutamatergic N-methyl-d-aspartate (NMDA) receptor in which we propose to identify new variants in the NMDAR1 gene and test for association with schizophrenia. We will also examine the role of allelic variation in the GABA receptor system. Finally, we are investigating selected linkage markers for association with schizophrenia using the Transmission Disequilibrium Test (TDT). This work is being conducted in collaboration with David Goldman, Chief of the Laboratory of Neurogenetics, NIAAA> 2) Psychoactive drug response and allelic variation -- We are examining allelic variants in the serotonin, dopamine, NMDAR1 and GABA receptor systems to test for association with typical and atypical drug response. We also have conducted pharmacological challenge studies with the NMDA antagonist ketamine and are investigating whether allelic variation may contribute to variation in behavioral, metabolic and neuroendocrinological response. These series of investigations are intended to provide informative data on the molecular basis of schizophrenia and the marked inter-individual differences in drug response.